Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress

Authors

Ekaterina D. Korobkina, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Camila Martinez Calejman, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
John A. Haley, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Miranda E. Kelly, Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
Huawei Li, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Maria Gaughan, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Qingbo Chen, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Matthew D. Lynes, MaineHealth Institute for ResearchFollow

Document Type

Article

Publication Date

10-14-2024

Institution/Department

Center for Molecular Medicine

Journal Title

Nature metabolism

Abstract

Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.

Recommended Citation

Korobkina, Ekaterina D.; Calejman, Camila Martinez; Haley, John A.; Kelly, Miranda E.; Li, Huawei; Gaughan, Maria; Chen, Qingbo; and Lynes, Matthew D., "Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress" (2024). MaineHealth Maine Medical Center. 3821.
https://knowledgeconnection.mainehealth.org/mmc/3821